Project Summary The long term goal of our laboratory is to study the pathogenic mechanisms induced by environmental toxicants, genetic mutations and gene-environment interactions in Parkinson?s disease (PD) with the ultimate goal of developing disease-modifying therapeutics for this brain disorder. Overall, our research projects address the following fundamental questions: 1) Gene- environment interactions: Do mutations linked to PD render dopamine neurons more susceptible to environmental toxicants? 2) Glia-neuron interactions: How do glial cells contribute to the vulnerability of dopamine neurons in PD? 3) Excessive mitochondrial fission has been demonstrated in genetic and toxicant-induced models of PD. Can mitochondrial fission and fusion be targeted for PD treatment? These research projects have been supported by NIEHS since 2006. This R35 proposal will be built upon the strength, expertise, experimental models and other resources generated from the NIEHS funded projects in our laboratory to take our work to the next transformative level. The primary goal of this R35 proposal is to demonstrate that neurotoxicity induced by neurotoxicants such as manganese (Mn) alone or in combination with other factors (?-synuclein and gastric bacteria) linked to PD can be mitigated by reducing the function of dynamin related protein-1 (Drp1), which is typically known as a mitochondrial fission protein. However, our recent findings have led us to unexpected and exciting mechanism of Drp1 through autophagy. Combined with our recent discoveries that neurotoxicants such as Mn and paraquat impair autophagy at a low and sub-lethal concentration, our vision is that Drp1 plays a central role in pathogenic mechanism and this protein can be targeted for PD therapy. Over the next eight years, this R35 will give us the flexibility and power to fully investigate the extensive involvement of Drp1 in neurotoxicity mediated by glia-neuron interactions, gene-environment interactions and gastric bacteria that have been linked to PD. This proposal utilizes a transdisciplinary approach from a team of accomplished investigators with relevant established track-records, a wide range of chemical and genetic tools, high standard techniques and innovative experimental models for molecular target manipulations with functional studies at cellular, circuit and whole animal levels. Completion of this project will provide paradigm shifts in our understanding of how Drp1 mediates neurotoxicity through a wide range of toxic insults.